Analysis of function of Cdx2 in gastric mucosal stem cells

Cdx2在胃粘膜干细胞中的功能分析

• 批准号: 20590341
• 负责人: YOKOZAKI Hiroshi
• 金额: $ 3.16万
• 依托单位: Kobe University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 财政年份: 2008
• 资助国家: 日本
• 起止时间: 2008 至 2010
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-20590341/
• 关键词: 病理学; 胃癌; 幹細胞; Cdx2; 分化; 増殖; 腸上皮化生; 異時多発胃癌

Introduction of PTEN expression vectors into TMK-1 gastric cancer cell line revealed that wild type PTEN induced the expressions of Cdx2 as well as intestinal type claudins (claudin-3 and -4). Direct binding of Cdx2 to the promoter region of intestinal claudins was confirmed by chromatin immunoprecipitation. Inverse correlation was observed between the expression levels of nuclear PTEN and phosphorylated Akt in human gastric cancer tissues. Cases with negative nuclear PTEN expression had poor prognosis and infrequent intestinal differentiation. These indicated that activity of Cdx2, inducing the differentiation of gastric cancer, requires the active PTEN phosphatase. Introduction of Cdx2 in the CD133 positive SW480 cells induced growth inhibition, morphological change and suppression of tumorigenesis. Microarray analysis showed that CD133 positive cells express higher levels of TGF-β receptors which was reduced by Cdx2 transfection suggesting the higher sensitivity to TGF-β may required for the maintenance of steaminess of the cancer cells. In the three dimensional culture, TGF-β suppressed the tubular elongation or branching with the induction of Snail at the surface of tumor sphere. Enhanced Snail expression induced by TGF-β was confirmed at the tumor budding of invasion front of the colorectal cancer suggesting the close correlation of Snail expression and reacquisition of stemness of cancer cells.

将PTEN表达载体导入TMK-1胃癌细胞，发现野生型PTEN可诱导CDX2和肠型claudins(claudin-3和-4)的表达。染色质免疫沉淀证实了CDX2与肠道Claudins启动子区域的直接结合。人胃癌组织中核PTEN和磷酸化Akt的表达水平呈负相关。PTEN核表达阴性者预后较差，肠道分化较少。这表明，CDX2的活性诱导胃癌分化需要活性的PTEN磷酸酶。在CD133阳性的SW480细胞中导入CDX2后，细胞的生长受到抑制，细胞形态发生改变，成瘤受到抑制。基因芯片分析显示，CD133阳性细胞表达较高水平的转化生长因子-β受体，该受体被CDX2基因转染组降低，提示肿瘤细胞对转化生长因子-β具有较高的敏感性可能是维持癌细胞热稳定性所必需的。在三维培养中，转化生长因子-β在蜗牛的诱导下抑制了肿瘤球体表面的管状延长或分支。在结直肠癌侵袭前沿的肿瘤萌芽部位证实了转化生长因子-β诱导的Snail表达增强，提示Snail的表达与癌细胞的再获得密切相关。

项目成果

The tumor suppressing pathway of WW domain containing oxidoreductase (WWOX) in human colorectal carcinogenesis

含WW结构域的氧化还原酶(WWOX)在人结直肠癌发生中的抑癌途径

• 发表时间: 2009
• 作者: 松下麻衣、仙波秀峰、横崎宏;他
• 通讯作者: 他

ヒト大腸癌における癌制御遺伝子WW domain containing oxidoreductase(WWOX)シグナル経路についての検討

含氧化还原酶 (WWOX) 信号通路的癌症调控基因 WW 结构域在人结直肠癌中的研究

• 发表时间: 2009
• 作者: 松下麻衣、仙波秀峰、横崎宏;他
• 通讯作者: 他

Regulation of PTEN expression by the AWI/SNF chromatin-remodelling protein BRG1 in human colorectal carcinoma cells.

人结直肠癌细胞中 AWI/SNF 染色质重塑蛋白 BRG1 对 PTEN 表达的调节。

• 发表时间: 2011
• 期刊: Br J Cancer
• 作者: Watanabe T;Semba S;Yokozaki H
• 通讯作者: Yokozaki H

Negativre gulation of the tight junction protein tricellulin by snail-induced epithelial- mesenchymal transition in gastric carcinoma cells.

蜗牛诱导的胃癌细胞上皮-间质转化对紧密连接蛋白三纤维素的负调节。

• 发表时间: 2010
• 期刊: Pathobiology 77巻
• 作者: Masuda R;Semba S;Mizuuchi E;Yanagihara K;Yokozaki H
• 通讯作者: Yokozaki H

Prognostic significance of intestinal claudins in high-risk synchronous and metachronous multiple gaslric epithelial neoplasias after initial endoscopic submucosal dissection.

肠粘蛋白在初次内镜粘膜下剥离术后高危同步和异时多发性胃上皮肿瘤中的预后意义。

• 发表时间: 2008
• 期刊: Pathology Inlernational 第58巻・第6号
• 作者: Nakayama F;Semba S;Usami Y;Chiba H;Sawada N;Yokozaki H;Satake S;Ito A;Nakayama S;Koma Y;Semba S
• 通讯作者: Semba S